Abstract
Background and Objectives Recent outbreaks of Zika virus (ZIKV) in South and Central America have highlighted significant neurologic side effects. Concurrence with the inflammatory neuropathy Guillain-Barré syndrome (GBS) is observed in 1:4,000 ZIKV cases. Whether the neurologic symptoms of ZIKV infection are immune mediated is unclear. We used rodent and human live cellular models to screen for anti-peripheral nerve reactive IgG and IgM autoantibodies in the sera of patients with ZIKV with and without GBS.
Methods In this study, 52 patients with ZIKV-GBS were compared with 134 ZIKV-infected patients without GBS and 91 non-ZIKV controls. Positive sera were taken forward for target identification by immunoprecipitation and mass spectrometry, and candidate antigens were validated by ELISA and cell-based assays. Autoantibody reactions against glycolipid antigens were also screened on an array.
Results Overall, IgG antibody reactivities to rat Schwann cells (SCs) (6.5%) and myelinated cocultures (9.6%) were significantly higher, albeit infrequent, in the ZIKV-GBS group compared with all controls. IgM antibody immunoreactivity to dorsal root ganglia neurones (32.3%) and SCs (19.4%) was more frequently observed in the ZIKV-GBS group compared with other controls, whereas IgM reactivity to cocultures was as common in ZIKV and non-ZIKV sera. Strong axonal-binding ZIKV-GBS serum IgG antibodies from 1 patient were confirmed to react with neurofascin 155 and 186. Serum from a ZIKV-infected patient without GBS displayed strong myelin-binding and putative antilipid antigen reaction characteristics. There was, however, no significant association of ZIKV-GBS with any known antiglycolipid antibodies.
Discussion Autoantibody responses in ZIKV-GBS target heterogeneous peripheral nerve antigens suggesting heterogeneity of the humoral immune response despite a common prodromal infection.
Glossary
- ALCAM=
- activated leukocyte cell adhesion molecule;
- ANOVA=
- analysis of variance;
- ANXA2=
- annexin A2;
- AMAN=
- acute motor axonal form of GBS;
- AXL=
- Axl receptor tyrosine kinase;
- CNTN1=
- contactin 1;
- DENV=
- dengue virus;
- DPYSL2=
- dihydropyrimidinase-related protein 2;
- DRG=
- dorsal root ganglia;
- Fc=
- fragment crystalizable region (of antibody);
- GBS=
- Guillain-Barré syndrome;
- GFRA1=
- glial cell-derived neurotrophic factor family receptor alpha-1;
- hiPSC=
- human induced pluripotent stem cell;
- HRP=
- horse radish peroxidase;
- IgG=
- immunoglobulin G;
- IgM=
- immunoglobulin M;
- ITGA7=
- integrin alpha 7;
- L1CAM=
- neural cell adhesion molecule L1;
- MS/MS=
- tandem mass spectrometry;
- MOPS=
- 3-(N-morpholino)propanesulfonic acid;
- NCAM1=
- neural cell adhesion molecule 1;
- NEP=
- neprilysin;
- NF155=
- neurofascin 155 isoform;
- NF186=
- neurofascin 186 isoform;
- NF200=
- neurofilament heavy chain (200 kDa);
- NFASC=
- neurofascin;
- NHS=
- normal human serum;
- NKCC1=
- solute carrier Na-K-2Cl cotransporter 1;
- NrCAM=
- neuronal cell adhesion molecule;
- PRX=
- periaxin;
- SC=
- Schwann cell;
- SEM=
- standard error of the mean;
- TGFBR3=
- transforming growth factor receptor type 3;
- VINC=
- vinculin;
- ZIKV=
- Zika virus;
- ZIKV-CON=
- ZIKV-infected patients without neurologic complications;
- ZIKV-OND=
- ZIKV infection and other inflammatory neurologic diseases
Footnotes
↵* These authors contributed equally to this work as co–first authors.
↵† These authors contributed equally to this work as co–senior authors.
Go to Neurology.org/NN for full disclosures. Funding information is provided at the end of the article.
The Article Processing Charge was funded by the authors.
Previously published at medRxiv doi: 10.1101/2021.10.28.21265167.
Submitted and externally peer reviewed. The handling editor was Marinos C. Dalakas, MD, FAAN.
- Received December 5, 2022.
- Accepted in final form September 1, 2022.
- Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
This is an open access article distributed under the terms of the Creative Commons Attribution License 4.0 (CC BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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